Benzopyrancarboxamide derivatives, salts thereof, process for the preparation of same and use thereof

ABSTRACT

There are disclosed a benzopyrancarboxamide derivative of the formula ##STR1## wherein R 1  is hydrogen atom or a lower alkyl group; R 2  is hydrogen atom, a lower alkyl group, halogen atom, an amino radical or an acylamino group; R 3  is hydrogen atom, a lower alkyl group, a lower alkoxy group or halogen atom; dotted line is a possible double bond; and n is an integer of 1-5, 
     and a pharmacologically acceptable salt of the compound, a process for the preparation of the compound and salt as well as use thereof.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel benzopyrancarboxamide derivativesor 1-azabicyclo 3.3.0!octan derivatives, salts thereof, process for thepreparation of same, and use thereof, namely a medicine for improvinghypermotility of digestive tract, which contains the compound or salt asan effective ingredient.

2. Related Arts

Since 4-amino-5-chloro-N- (2-diethylamino)ethyl!-2 -methoxybenzamideGeneral name:Metoclopramide ("The Merck Index", 10th Ed. 6063)! had beendeveloped in the 1960s, as an agent for improving hypermotility ofdigestive tract or anti-vomiting agent, various benzamide derivativeshave been synthesized to evaluate pharmacological effect thereof. Themain object for developing such derivatives lies in moderating a sideeffect of Metoclopramide to central nerve system due to itsanti-dopamine action, namely extrapyramidal disorder and cryptorrhea(lactation and prolactinemia), and recent years, various reports havebeen issued on development of derivatives having antagonism to serotoninreceptor.

A relation between a selective pharmacological activity and structure ofthese benzamide derivatives has not sufficiently been elucidated, but ithas been recognized that a mutual relation between a substituent toamide nitrogen and alkoxy group at 2-position is important for instance,Jap. Pat. Sho 62 (A.D. 1987) - 129279(A) and "J. Med. Chem.", Vol. 34,page 616 (1991)!. Under such a technical notion, carboxamide derivativesof benzofuran, benzopyran or indole have been studied, as compoundsanalogous to the benzamide derivatives Jap. Pat. Sho 60 (A.D. 1985) -169473(A), Sho 62 (A.D. 1987) - 234083(A), Hei 1 (A.D. 1989) -104072(A), Hei 1 (A.D. 1989) - 110684(A), Hei 1 (A.D. 1989) - 168686(A),Hei 1 (A.D. 1989) - 501226(A), Hei 2 (A.D. 1990) - 289566(A), Hei 4(A.D. 1992) - 211685(A), Hei 4 (A.D. 1992) - 295476(A), and WO90/06113!.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a novel compound whichhas excellent or powerful action to activate 5-HT₄ receptor and improvehypermotility of digestive tract and no or weak side effect to centralnerve system, and thus is excellent in effectiveness and safety.

The inventors have energetically studied and investigated to finallyfind out that certain benzopyrancarboxamide or 1-azabicyclo 3.3.0!octanderivatives are suitable for attaining the object, so that the inventionwas established.

The benzopyrancarboxamide or 1-azabicyclo 3.3.0!octan derivativesaccording to the invention are shown by a formula of ##STR2## wherein R¹is hydrogen atom or an lower alkyl group; R² is hydrogen atom, halogenatom, a lower alkyl group, amino radical or an acylamino group; R³ ishydrogen atom, a lower alkyl group, a lower alkoxy group or halogenatom; dotted line means a possible double bond; and n is an integer of1-5.

According to a process of the invention, the derivatives (I) and saltsthereof can be prepared by reacting a compound of the formula ##STR3##wherein R¹, R², and R³ have the meanings as referred to, or a reactivederivative thereof with a compound of the formula ##STR4## wherein n hasthe meaning as referred to, and if necessary, converting a reactionproduct into the salt.

In connection with the compounds (I), the lower alkyl group is such astraight- or branched-chain alkyl group having 1-6 carbon atoms asmethyl, ethyl, propyl, isopropyl, butyl, heptyl and hexyl radicals. Asexamples of the acylamino group, acetylamino and propionylamino radicalsmay be listed. The lower alkoxy group may be of a straight- orbranched-chain alkoxy group having 1-6 carbon atoms as methoxy, ethoxy,propoxy, isopropoxy, butoxy, heptyloxy and hexyloxy radicals. Thehalogen atom may be of fluorine, chlorine, bromine or iodine.

The salt of the compounds (I) means, of course, pharmacologicallyacceptable one, and hydrochloric acid, sulfuric acid, hydrobromic acidor the like inorganic acid; and fumaric acid, oxalic acid, maleic acid,malic acid, tartaric acid, methanesulfonic acid or the like organic acidcan be listed as that for forming the salt.

As the reactive derivative of compound (I), a lower alkyl ester, activeester, acid anhydride, acid halide (especially acid chloride) or thelike may be listed. As the active ester, p-nitrophenyl ester,2,4,5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester,N-hydroxysuccinic imide ester, N-hydroxy- 5-norbornen-2,3-dicarboxyimideester, N-hydroxypiperidine ester, 8-hydroxyquinoline ester,2-hydroxyphenyl ester, 2-hydroxy-4,5-dichlorophenyl ester,2-hydroxypyridine ester and 2-pyridylthiol ester can be exemplarylisted. As the acid anhydride, a symmetrical acid anhydride or mixedacid anhydride can be employed. As the mixed acid anhydride, any mixtureof ethyl chlorocarbonate, isobutyl chlorocarbonate, benzylchlorocarbonate, phenyl chlorocarbonate and the like chlorocarbonic acidesters, or a mixture of the ester with an alkane acid such as isovaleicacid, pivalic acid or the like.

For the reaction between the compounds (II) and (III), a dehydrationcondensing agent may be added. Such an agent may be listed therefor asdicyclohexylcarbodiimide, hydrochloride of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonyldiimidazole,1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or the like organiccondensing agent; and phosphorous trichloride, phosphorouspentachloride, phosphorous oxychloride, thionyl chloride, silicontetrachloride or the like inorganic condensing agent.

The reaction of the compound (II) or its reactive derivative with thecompound (III) can be carried out by stirring for 0.5-24 hours at-30-+150° C. in an inert solvent. Such a solvent may be exemplary listedas benzene, toluene, xylene or the like aromatic hydrocarbon;diethylether, tetrahydrofuran, dioxane or the like ether; methylenechloride, chloroform or the like halogenated hydrocarbon; pyridine,quinoline, ethyl acetate, acetonitrile, dimethylformamide,dimethylsulfoxide, acetone, ethylene glycol, water, or a mixture of theabove. If necessary, the reaction may be carried out in the presence ofa base such as sodium carbonate, potassium carbonate or the like alkalicarbonate; sodium hydrogen carbonate or the like alkali hydrogencarbonate; sodium hydroxide, potassium hydroxide or the like alkalihydroxide; triethylamine, N-methylmorpholine, N,N-dimethylaniline,pyridine, quinoline or the like tertiary amine. In lieu of separateaddition of the base, the compound (III) may be used in an excessamount.

The starting compounds (II) and (III) can be synthesized in accordancewith methods described, for instance, in "Abstract of the 98th AnnualLecture Meeting in the Pharmacological Society of Japan", page 223(1978) (for compounds II) and Jap. Pat. Sho 62 (A.D. 1987) - 277376(A),Hei 2 (A.D. 1990) - 289566(A), Hei 4 (A.D. 1992) - 211685(A) and WO93/016072 (for compounds III).

When a medicine shall be prepared by using the compound (I) or saltthereof as an effective ingredient, there is no limitation in form ofthe medicine and thus it can be made into a tablet, pill, capsule,powder, granule, suppository of the like solid preparation; or asolution, suspension, emulsion or the like liquid preparation. Forpreparing the solid preparation, a starch, lactose, glucose, calciumphosphate, magnesium stearate, carboxymethyl cellulose or the likefiller can be used and if necessary, a lubricant, disintegrator, coatingagent, coloring matter may also be used. The liquid preparation maycontain a stabilizer, dissolution aid, suspending agent, emulsifier,buffer, preservative or the like.

An amount of dose of the compound (I) or salt thereof varies dependingon a selected kind of the same, form of the medicine, symptom, age of apatient and other factors, but in general, such a range of about0.01--about 50 mg/day is preferable for an adult.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will now be further explained in more detail withreference to Manufacturing Examples, Pharmacological Test Examples andMedicine Preparation Examples.

EXAMPLE 1 5-Amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide·1/2fumarate

Into an agitating solution of5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid (100 mg)in absolute tetrahydrofuran (1 ml), was added 1,1'-carbonylimidazole (72mg) and after lapsed 1 hour, a solution of 5-(2-aminoethyl)-1-azabicyclo3.3.0!octane (62 mg) was added therein to reflux for 1 hour. Aftercooled, the solvent was distilled out in vacuo, a residue was dissolvedinto chloroform, washed with saturated sodium hydrogen carbonatesolution and then water, and thereafter, the solvent was distilled outin vacuo. The resulting residue was refined by alumina columnchromatography (developing solvent:chloroform) to afford 137 mg of5-amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide.The compound was treated with fumaric acid in ethanol to quantitativelyobtain the titled salt.

Melting point: 222°-229° C. (dec.).

Mass spectrum (EI/DI) m/z:

363 (M⁺), 110.

NMR spectrum (DMSO-d₆) δ ppm:

1.62-2.00 (10H, m),

2.49 (2H, t),

2.74 (2H, m),

3.11 (2H, m),

3.32 (2H, m),

4.19 (2H, t),

5.50 (2H, broad s),

6.45 (1H, s),

7.62 (1H, s),

8.37 (1H, broad t).

EXAMPLE 2 5-Amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2-methyl-2H-1-benzopyran-8-carboxamide·1/2fumarate

By treating as described in Example 1 excepting that5-amino-6-chloro-3,4-dihydro-2-methyl-2H-1-benzopyran-8-carboxylic acid(100 mg) was selected as a starting compound, 5-amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2-methyl-2H-1-benzopyran-8-carboxamide(83 mg) was obtained. The compound was treated with fumaric acid inethanol to quantitatively obtain the titled salt.

Melting point: 221°-225° C. (dec.).

Mass spectrum (EI/DI) m/z:

377 (M⁺), 110.

NMR spectrum (DMSO-d₆) δ ppm:

1.38 (3H, d),

1.57-1.87 (11H, m),

2.05 (1H, m),

2.49 (2H, m),

2.71 (2H, m),

3.00-3.40 (4H, m),

4.20 (1H, m),

5.51 (2H, broad s),

6.44 (1H, s),

7.60 (1H, s),

8.02 (1H, broad t).

EXAMPLE 3 5-Amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-2H-1-benzopyran-8-carboxamide·1/2fumarate

By treating as described in Example 1 excepting that5-amino-6-chloro-2H-1-benzopyran-8-carboxylic acid (100 mg) was selectedas a starting compound, 5-amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-2H-1-benzopyran-8-carboxamide (135 mg)was obtained. The compound was treated with fumaric acid in ethanol toquantitatively obtain the titled salt.

Melting point: 221°-225° C. (dec.).

Mass spectrum (EI/DI) m/z:

361 (M⁺), 110.

NMR spectrum (DMSO-d₆) δ ppm:

1.50-1.89 (10H, m),

2.74 (2H, m),

3.10 (2H, m),

3.60 (2H, m),

4.75 (2H, double d),

5.90 (3H, m),

6.45 (1H, s),

6.81 (1H, d),

7.60 (1H, s),

8.34 (1H, broad t).

EXAMPLE 4 N- 2-(1-Azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-2H-1-benzopyran-8-carboxamide·1/2fumarate

By treating as described in Example 1 excepting that3,4-dihydro-2H-1-benzopyran-8-carboxylic acid (100 mg) was selected as astarting compound, N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-2H-1-benzopyran-8-carboxamide (165mg) was obtained.

The compound was treated with fumaric acid in ethanol and lyophilized toquantitatively obtain the titled salt.

Mass spectrum (EI/DI) m/z:

314 (M⁺), 110.

¹ H-NMR spectrum (CDCl₃) δ ppm:

1.77-2.18 (12H, m),

2.76-2.84 (4H, m),

3.52-3.71 (4H, m),

4.32 (2H, t),

6.76 (1H, s),

6.90 (1H, dd),

7.10 (1H, dd),

7.96 (1H, dd),

8.20 (1H, broad s).

EXAMPLE 5 N- 2-(1-Azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-5-chloro-2H-1-benzopyran-8-carboxamide·fumarate

By treating as described in Example 1 excepting that5-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid (100 mg) wasselected as a starting compound, N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-5-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide(139 mg) was obtained. The compound was treated with fumaric acid inethanol and crystallized from ethyl ether to quantitatively obtain thetitled salt.

Melting point: 171°-173° C. (dec.).

Mass spectrum (EI/DI) m/Z:

348 (M⁺), 110.

¹ H-NMR spectrum (CDCl₃) δppm:

1.87-2.30 (12H, m),

2.73-2.95 (4H, m),

3.52-3.59 (2H, m),

3.85-3.94 (2H, m),

4.29 (2H, t),

6.79 (2H, s),

7.00 (1H, d),

7.90 (1H, d),

8.03 (1H, broad s).

EXAMPLE 6 N- 2-(1-Azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-chloro-2H-1-benzopyran-8-carboxamide·1/2fumarate

By treating as described in Example 1 excepting that6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid (100 mg) wasselected as a starting compound, N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide(143 mg) was obtained. The compound was treated with fumaric acid inethanol and lyophilized to quantitatively obtain the titled salt.

Mass spectrum (EI/DI) m/z:

348 (M⁺), 110.

¹ H-NMR spectrum (CDCl₃) δ ppm:

1.80-2.18 (12H, m),

2.73-2.85 (4H, m),

3.50-3.72 (4H, m),

4.29-4.33 (2H, m),

6.75 (1H, s),

7.06 (1H, d),

7.92 (1H, d),

8.17 (1H, broad s).

EXAMPLE 7 N- 2-(1-Azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-methoxy-2H-1-benzopyran-8-carboxamide·1/2fumarate

By treating as described in Example 1 excepting that3,4-dihydro-6-methoxy-2H-1-benzopyran-8-carboxylic acid (100 mg) wasselected as a starting compound, N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-methoxy-2H-1-benzopyran-8-carboxamide(168 mg) was obtained.

The compound was treated with fumaric acid in ethanol and lyophilized toquantitatively obtain the titled salt.

Mass spectrum (EI/DI) m/z:

344 (M⁺), 110.

¹ H-NMR spectrum (CDCl₃) δ ppm:

1.77-2.17 (12H, m),

2.74-2.84 (4H, m),

3.51-3.71 (4H, m),

3.77 (3H, s),

4.25-4.29 (2H, m),

6.68 (1H, d),

6.76 (1H, s),

7.54 (1H, d),

8.30 (1H, broad s).

EXAMPLE 8 N- 2-(1-Azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-5-methyl-2H-1-benzopyran-8-carboxamide·1/2fumarate

By treating as described in Example 1 excepting that3,4-dihydro-5-methyl-2H-1-benzopyran-8-carboxylic acid (100 mg) wasselected as a starting compound, N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-5-methyl-2H-1-benzopyran-8-carboxamide(146 mg) was obtained.

The compound was treated with fumaric acid in ethanol and lyophilized toquantitatively obtain the titled salt.

Mass spectrum (EI/DI) m/z:

328 (M⁺), 110.

¹ H-NMR spectrum (CDCl₃) δ ppm:

1.77-2.21 (12H, m),

2.18 (3H, s),

2.58-2.63 (2H, m),

2.75-2.84 (2H, m),

3.51-3.71 (4H, m),

4.24-4.28 (2H, m),

6.76 (1H, s),

6.79 (1H, d),

7.88 (1H, d),

8.19 (1H, broad s).

EXAMPLE 9 N- 2-(1-Azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-methyl-2H-1-benzopyran-8-carboxamide·1/2fumarate

By treating as described in Example 1 excepting that3,4-dihydro-6-methyl-2H-1-benzopyran-8-carboxylic acid (100 mg) wasselected as a starting compound, N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-methyl-2H-1-benzopyran-8-carboxamide(160 mg) was obtained.

The compound was treated with fumaric acid in ethanol and lyophilized toquantitatively obtain the titled salt.

Mass spectrum (EI/DI) m/z:

328 (M⁺), 110.

¹ H-NMR spectrum (CDCl₃) δ ppm:

1.47-2.28 (12H, m),

2.25 (3H, s),

2.72-2.82 (4H, m),

3.50-3.67 (4H, m),

4.26-4.30 (2H, m),

6.75 (1H, s),

6.91 (1H, d),

7.77 (1H, d),

8.21 (1H, broad s).

EXAMPLE 10 5-Acetylamino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide·fumarate

By treating as described in Example 1 excepting that5-acetylamino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid(100 mg) was selected as a starting compound, 5-acetylamino-N-2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide(163 mg) was obtained.

The compound was treated with fumaric acid in ethanol and crystallizedfrom ethyl ether to quantitatively obtain the titled salt.

Melting point: >195° C. (dec.)

Mass spectrum (EI/DI) m/z:

405 (M⁺), 110.

¹ H-NMR spectrum (CDCl₃) δ ppm:

1.79-2.07 (12H, m),

2.19 (3H, s),

2.70-2.86 (4H, m),

3.49-3.55 (4H, m),

4.29-4.32 (2H, m),

6.72 (1H, s),

7.99 (1H, s),

8.38 (1H, broad s),

9.06 (1H, broad s).

Pharmacological Test Example 1

(Agonisting action to 5-HT₄ receptor)

Each of the compounds obtained by Examples and Cisapride (exemplar knowncompound which has been said as having a strong agonisting action to5-HT₄ receptor) were selected as Test Compounds and Control compound,and agonisting action thereof was checked in accordance with the methoddescribed by Baxter et al. "Naunyn-Schmiederberg's Arch. Pharmacol.",Vol. 343, page 439 (1991)!.

Namely, a relaxation of the Test and Control compounds in variousconcentration showing to carbachol contradiction of a muscular sample ofmucous membrane in esophgus exentrated from a rat was checked tocalculate a concentration causing 50% relaxation and compared with itsnegative logarithm (_(P) EC₅₀). Results are shown in following Table 1.Therefrom, it has been found that the compounds according to theinvention show the agonisting action to 5-HT₄ receptor, which iscompatible to or excellent than the Control Compound.

                  TABLE 1    ______________________________________           Compound                   .sub.P EC.sub.50    ______________________________________           Example           1       8.3           2       7.7           3       7.6           4       4.9           5       4.6           6       4.9           7       4.6           8       4.7           9       4.8           10      5.1           Cisapride                   7.4    ______________________________________

Pharmacological test Example 2

(Anti-dopamine action)

The compounds obtained by Examples as well as known compound(Metoclopramide) were selected as Test and Control Compounds,respectively. The compound was orally administered to rats to observefor 2 days general symptoms including catalepsy and blepharoptosis dueto antagonistic action of the compound to dopamine D₂ receptor.

In each case of the compounds according to the invention, no influenceto central nerve system due to anti-dopamine action can be recognized insingle administration of 500 mg/kg, but in case of Metoclopramide,somewhat remarkable influence was recognized in single administration of100 mg/kg.

Medicine Preparation Example 1 (Tablet)

Tablets were prepared in conventional manner and by using followingingredients.

    ______________________________________    Fumarate (Example 1)  2.0 (mg)    Lactose              136.0    Corn starch           60.0    Magnesium stearate    2.0                         200.0 mg/tablet    ______________________________________

Medicine Preparation Example 2 (Injection)

An injection was prepared in conventional manner and by using followingingredients. The injection was charged into ampules under asepticcondition to heat seal the ampules. When it shall be used, the solutionin the ampule may be diluted with a saline for injection.

    ______________________________________    Fumarate (Example 2)  0.05 (mg)    Sodium chloride       8.00    Distilled water for injection                          Remainder                          1.0 ml/ampule    ______________________________________

What is claimed is:
 1. A benzopyrancarboxamide derivative of the formula##STR5## wherein R¹ is hydrogen atom or a lower alkyl group; R² ishydrogen atom, a lower alkyl group, halogen atom, an amino radical or anacylamino group; R³ is hydrogen atom, a lower alkyl group, a loweralkoxy group or halogen atom; dotted line is a possible double bond; andn is an integer of 1-5, or a pharmacologically acceptable salt of thecompound.
 2. A benzopyrancarboxamide derivative as claimed in claim 1,wherein said derivative is selected from the group consisting of(a)5-amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide,(b) 5-amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2-methyl-2H-1-benzopyran-8-carboxamide,(c) 5-amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-2H-1-benzopyran-8-carboxamide, (d) N-2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-2H-1-benzopyran-8-carboxamide, (e)N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-5-chloro-2H-1-benzopyran-8-carboxamide,(f) N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-chloro-2H-1-benzopyran-8-carboxamide,(g) N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-methoxy-2H-1-benzopyran-8-carboxamide,(h) N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl-3,4-dihydro-5-methyl-2H-1-benzopyran-8-carboxamide,(i) N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-methyl-2H-1-benzopyran-8-carboxamide,and (j) 5-acetylamino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)-ethyl!-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide.3. A process for the preparation of a benzopyrancarboxamide derivativeof the formula ##STR6## wherein R¹ is hydrogen atom or a lower alkylgroup; R² is hydrogen atom, a lower alkyl group, halogen atom, an aminoradical or an acylamino group; R³ is hydrogen atom, a lower alkyl group,a lower alkoxy group or halogen atom; dotted line is a possible doublebond; and n is an integer of 1-5, or a pharmacologically acceptable saltof the compounds, which comprises a step of reacting a compound of theformula ##STR7## wherein R¹, R² and R³ have the meanings as referred to,or a reactive derivative thereof with a compound of the formula ##STR8##wherein n has the meaning as referred to, and if necessary, converting areaction product into the salt.
 4. A pharmaceutical composition forimproving hypermotility of a digestive tract, comprising an effectiveamount of a benzopyrancarboxamide derivative of the formula ##STR9##wherein R¹ is hydrogen atom or a lower alkyl group; R² is hydrogen atom,a lower alkyl group, halogen atom, an amino radical or an acylaminogroup; R³ is hydrogen atom, a lower alkyl group, a lower alkoxy group orhalogen atom; dotted line is a possible double bond; and n is an integerof 1-4, or a pharmacologically acceptable salt of the compound, inassociation with a pharmaceutically acceptable carrier or excipient. 5.The pharmaceutical composition as claimed in claim 4, wherein saidbenzopyrancarboxamide derivative is selected from the group consistingof(a) 5-amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide,(b) 5-amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-3,4-dihydro-2-methyl-2H-1-benzopyran-8-carboxamide,(c) 5-amino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-6-chloro-2H-1-benzopyran-8-carboxamide, (d) N-2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-2H-1-benzopyran-8-carboxamide, (e)N- 2-(1-azabicyclo 3.3.0!octan-5-yl)ethyl!-3,4-dihydro-5chloro-2H-1-benzopyran-8-carboxamide, (f) N-2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-chloro-2H-1-benzopyran-8-carboxamide,(g) N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-methoxy-2H-1-benzopyran-8-carboxamide,(h) N- 2-(1-azabicyclo3.3.0!octan-5-yl)ethyl-3,4-dihydro-5-methyl-2H-1-benzopyran-8-carboxamide,(i) N- 2-(1-azabicyclo 3.3.0!octan-5-yl)ethyl!-3,4-dihydro-6-methyl-2H-1-benzopyran-8-carboxamide, and (j) 5-acetylamino-N- 2-(1-azabicyclo3.3.0!octan-5-yl)-ethyl!-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide.6. A method for improving hypermotility of a digestive tract, comprisingadministrating to a patient in need of such treatment an effectiveamount of a benzopyrancarboxamide derivative of the formula ##STR10##wherein R¹ is hydrogen atom or a lower alkyl group; R² is hydrogen atom,a lower alkyl group, halogen atom, an amino radical or an acylaminogroup; R³ is hydrogen atom, a lower alkyl group, a lower alkoxy group orhalogen atom; dotted line is a possible double bond; and n is an integerof 1-5, or a pharmacologically acceptable salt of the compound, inassociation with a pharmaceutically acceptable carrier or excipient.